Use of 7h-pyrrollo{2,3-d}pyrimidine derivatives in the treatment of solid tumor diseases

ABSTRACT

Patients suffering from a solid tumor disease selected from carcinoma of the bladder, renal carcinoma, squamous cell carcinoma of the skin, head and neck cancer, especially squamous cell head and neck cancer, lung cancer, especially non small cell lung cancer (NSCLC), tumors of the gastrointestinal tract, glioma and mesothelioma or metastases of such solid tumor diseases are treated with a 7H-pyrrolo[2,3-d]pyrimidine derivative.

This invention relates to a method for the treatment of patientssuffering from a solid tumor disease selected from carcinoma of thebladder, renal carcinoma, squamous cell carcinoma of the skin, head andneck cancer, especially squamous cell head and neck cancer, lung cancer,especially non small cell lung cancer (NSCLC), tumors of thegastrointestinal tract, glioma and mesothelioma comprising administeringa 7H-pyrrolo[2,3-d]pyrimidine derivative, or a pharmaceuticallyacceptable salt thereof, in particular using an improved regimen for theadministration of such 7H-pyrrolo[2,3-d]pyrimidine derivative.

7H-pyrrolo[2,3-d]pyrimidine derivatives useful for treating tumordiseases and other conditions are, e.g., disclosed in U.S. Pat. No.6,140,332, which is here incorporated by reference in its entirety. Such7H-pyrrolo[2,3-d]pyrimidine derivatives are described in such patent tobe useful for the treatment of benign or malignant tumours being capableof effecting tumour regression and of preventing the formation of tumourmetastases and the growth of micrometastases. According to such patentsuch compounds can be used especially in the case of epidermalhyperproliferation (psoriasis), in the treatment of neoplasias ofepithelial character, e.g. mammary carcinomas, and in leukaemias.

Furthermore, U.S. Pat. No. 6,140,332 discloses that the7H-pyrrolo[2,3-d]pyrimidine derivatives are administered in the case ofan individual having a body weight of about 70 kg at a daily dose fromapproximately 0.1 grams to approximately 5 grams, preferably from about0.5 grams to 2 grams. It is not suggested that the7H-pyrrolo[2,3-d]pyrimidine derivative should be administered onalternate days.

Surprisingly, it was now found that 7H-pyrrolo[2,3-d]pyrimidinederivatives are suitable for the treatment of the solid tumor diseasesmentioned herein. Thus, the present invention relates to the use of a7H-pyrrolo[2,3-d]pyrimidine derivative, or a pharmaceutically acceptablesalt thereof, for the manufacture of a medicament for the treatment ofcarcinoma of the bladder, renal carcinoma, squamous cell carcinoma ofthe skin, head and neck cancer, especially squamous cell head and neckcancer, lung cancer, especially non small cell lung cancer (NSCLC),tumors of the gastrointestinal tract, glioma or mesothelioma.

Furthermore, the present invention relates to a method for the treatmentof patients suffering from a solid tumor disease selected from renalcarcinoma, squamous cell carcinoma of the skin, head and neck cancer,especially squamous cell head and neck cancer, lung cancer, especiallyNSCLC, tumors of the gastrointestinal tract, glioma and mesotheliomacomprising administering a 7H-pyrrolo[2,3-d]pyrimidine derivative, or apharmaceutically acceptable salt thereof, in particular using animproved regimen for the administration of such7H-pyrrolo[2,3-d]pyrimidine derivative as described herein.

The present invention further relates to a method of inhibitingmetastatic growth in a patient with a solid tumor disease as definedherein which comprises administering a pharmaceutically effective amountof a 7H-pyrrolo[2,3-d]pyrimidine derivative or a pharmaceuticallyacceptable salt thereof, to the patient, in particular using an improvedregimen for the administration of such 7H-pyrrolo[2,3-d]pyrimidinederivative as described herein.

In the present invention, the compound(R)-6-(4-hydroxy-phenyl)-4-[(1-phenyl-ethyl)-amino]-7H-pyrrolo[2,3-d]pyrimidine,or a pharmaceutically acceptable salt therof, is the preferred7H-pyrrolo[2,3-d]pyrimidine derivative, which compound is described inExample 39 of WO 97/02266. The compound is also known in the art as“PKI166” or “CGP 75166”.

Another aspect of the present invention is the use of7H-pyrrolo[2,3-d]pyrimidine derivative of formula I

wherein

-   R₁ and R₂ are each independently of the other hydrogen,    unsubstituted or substituted alkyl or cycloalkyl, a heterocyclic    radical bonded via a ring carbon atom, or a radical of the formula    R₄—Y—(C═Z)— wherein R₄ is unsubstituted, mono- or disubstituted    amino or a heterocyclic radical, Y is either not present or lower    alkyl and Z is oxygen, sulfur or imino, with the proviso that R₁ and    R₂ are not both hydrogen; or-   R₁ and R₂ together with the nitrogen atom to which they are attached    form a heterocyclic radical;-   R₃ is a heterocyclic radical or an unsubstituted or substituted    aromatic radical;-   G is C₁-C₇-alkylene, —C(═O)—, or C₁-C₆-alkylene-C(═O)— wherein the    carbonyl group is attached to the NR₁R₂ moiety;-   Q is —NH— or —O—, with the proviso that Q is —O— if G is —C(═O)— or    C₁-C₆-alkylene-C(═O)—; and-   X is either not present or C₁-C₇-alkylene, with the proviso that a    heterocyclic radical R₃ is bonded via a ring carbon atom if X is not    present;-   or a salt of the said compounds,    for the treatment of carcinoma of the bladder, renal carcinoma,    squamous cell carcinoma of the skin, tumors of the gastrointestinal    tract, mesothelioma, esophageal tumors, stomach cancer, small-bowel    tumors and large-bowel tumors such as polyps of the colon and    rectum, and anorectal cancer.

A further aspect of the present invention is a method of inhibitingmetastatic growth in a patient with a solid tumor disease selected fromcarcinoma of the bladder, renal carcinoma, squamous cell carcinoma ofthe skin, tumors of the gastrointestinal tract, mesothelioma, esophagealtumors, stomach cancer, small-bowel tumors and large-bowel tumors suchas polyps of the colon and rectum, and anorectal cancer which comprisesadministering to the patent a pharmaceutically effective amount of a7H-pyrrolo[2,3-d]pyrimidine derivative of formula I wherein R₁ and R₂are each independently of the other hydrogen, unsubstituted orsubstituted alkyl or cycloalkyl, a heterocyclic radical bonded via aring carbon atom, or a radical of the formula R₄—Y—(C═Z)— wherein R₄ isunsubstituted, mono- or disubstituted amino or a heterocyclic radical, Yis either not present or lower alkyl and Z is oxygen, sulfur or imino,with the proviso that R₁ and R₂ are not both hydrogen; or R₁ and R₂together with the nitrogen atom to which they are attached form aheterocyclic radical; R₃ is a heterocyclic radical or an unsubstitutedor substituted aromatic radical; G is C₁-C₇-alkylene, —C(═O)—, orC₁-C₆-alkylene-C(═O)— wherein the carbonyl group is attached to theNR₁R₂ moiety; Q is —NH— or —O—, with the proviso that Q is —O— if G is—C(═O)— or C₁-C₆-alkylene-C(═O)—; and X is either not present orC₁-C₇-alkylene, with the proviso that a heterocyclic radical R₃ isbonded via a ring carbon atom if X is not present; or a salt of the saidcompounds, for the treatment of carcinoma of the bladder, renalcarcinoma, squamous cell carcinoma of the skin, tumors of thegastrointestinal tract, mesothelioma, esophageal tumors, stomach cancer,small-bowel tumors and large-bowel tumors such as polyps of the colonand rectum, and anorectal cancer.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

As used herein, the expression “week” means seven consecutive days.Thus, a three week period is twenty-one consecutive days starting on anyday of the calendar week. The day that the first dose is given isconsidered to be the first day of the week. Any discussion usingcalendar weeks is intended to be for illustrative purposes only.

As used herein, the expression “mesothelioma” means a malignant tumorderived from mesothelial tissue (peritoneum, pleura, pericardium).

As used herein, the expression “glioma” preferably includes all primaryintrinsic neoplasms of the brain and spinal cord, e.g. astrocytomas,ependymomas, neurocytomas or meningiomas.

The term “tumors of the gastrointestinal tract” as used herein,includes, but is not limited to esophageal tumors, stomach cancer,small-bowel tumors and large-bowel tumors such as polyps of the colonand rectum, colorectal cancer and anorectal cancer.

As used herein, the expression “partial response” means a greater thanor equal to 50% reduction in measurable or evaluable disease in theabsence of progression in any particular disease site.

As used herein, the expression “stable disease” means a less than 50%decrease or less than 25% increase in measurable or evaluable disease.

Asymmetric carbon atoms of a compound of formula I that are optionallypresent may exist in the (R), (S) or (R,S) configuration, preferably inthe (R) or (S) configuration. Substituents at a double bond or a ringmay be present in cis- (═Z—) or trans (═E—) form. The compounds may thusbe present as mixtures of isomers or preferably as pure isomers.

Preferably alkyl contains up to 20 carbon atoms and is most preferablylower alkyl.

The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either unbranched or branched withsingle or multiple branching.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl or n-heptyl.

Alkyl R₁ and R₂ independently of each other are preferably methyl,ethyl, isopropyl or tert-butyl, especially methyl or ethyl.

Lower alkyl Y is preferably methyl, ethyl or propyl.

Lower alkoxy is for example ethoxy or methoxy, especially methoxy.

Substituted alkyl is preferably lower alkyl as defined above where oneor more, preferably one, substituents may be present, such as e.g.amino, N-lower alkylamino, N,N-di-lower alkylamino, N-loweralkanoylamino, N,N-di-lower alkanoylamino, hydroxy, lower alkoxy, loweralkanoyl, lower alkanoyloxy, cyano, nitro, carboxy, loweralkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthio,halogen or a heterocyclic radical.

Substituted alkyl R₁ and R₂ are independently of each other preferablyhydroxy-lower alkyl, N,N-di-lower alkylamino-lower alkyl ormorpholinyl-lower alkyl.

Preferably unsubstituted or substituted cycloalkyl R₁ or R₂ containsfrom 3 up to 20 carbon atoms and is especially unsubstituted or alsosubstituted C₃-C₆ cycloalkyl wherein the substituents are selected frome.g. unsubstituted or substituted lower alkyl, amino, N-loweralkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, N,N-di-loweralkanoylamino, hydroxy, lower alkoxy, lower alkanoyl, lower alkanoyloxy,cyano, nitro, carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, amidino, guanidino,ureido, mercapto, lower alkylthio, halogen or a heterocyclic radical.

Mono- or disubstituted amino is amino substituted by one or two radicalsselected independently of one another from e.g. unsubstituted orsubstituted lower alkyl.

Disubstituted amino R₄ is preferably N,N-di-lower alkylamino, especiallyN,N-dimethylamino or N,N-diethylamino.

A heterocyclic radical contains especially up to 20 carbon atoms and ispreferably a saturated or unsaturated monocyclic radical having from 4or 8 ring members and from 1 to 3 heteroatoms which are preferablyselected from nitrogen, oxygen and sulfur, or a bi- or tri-cyclicradical wherein, for example, one or two carbocyclic radicals, such ase.g. benzene radicals, are annellated (fused) to the mentionedmonocyclic radical. If a heterocyclic radical contains a fusedcarbocyclic radical then the heterocyclic radical may also be attachedto the rest of the molecule of formula I via a ring atom of the fusedcarbocyclic radical. The heterocyclic radical (including the fusedcarbocyclic radical(s) if present) is optionally substituted by one ormore, preferably by one or two, radicals such as e.g. unsubstituted orsubstituted lower alkyl, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, N,N-di-lower alkanoylamino, hydroxy,lower alkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro, carboxy,lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthio,or halogen.

Most preferably a heterocyclic radical is pyrrolidinyl, piperidyl, loweralkyl-piperazinyl, di-lower alkyl-piperazinyl, morpholinyl,tetrahydropyranyl, pyridyl, pyridyl substituted by hydroxy or loweralkoxy, or benzodioxolyl, especially pyrrolidinyl, piperidyl, loweralkyl-piperazinyl, di-lower alkyl-piperazinyl or morpholinyl.

A heterocyclic radical R₁ or R₂ is as defined above for a heterocyclicradical with the proviso that it is bonded to the rest of the moleculeof formula I via a ring carbon atom. Preferably a heterocyclic radicalR₁ or R₂ is lower alkyl-piperazinyl or especially preferredtetrahydropyranyl. If one of the two radicals R₁ and R₂ represents aheterocyclic radical, the other is preferably hydrogen.

A heterocyclic radical R₃ is as defined above for a heterocyclic radicalwith the proviso that it is bonded to Q via a ring carbon atom if X isnot present. Preferably a heterocyclic radical R₃ is benzodioxolyl,pyridyl substituted by hydroxy or lower alkoxy, or especially preferredindolyl substituted by halogen and lower alkyl. If R₃ is pyridylsubstituted by hydroxy then the hydroxy group is preferably attached toa ring carbon atom adjacent to the ring nitrogen atom.

A heterocyclic radical R₄ is as defined above for a heterocyclic radicaland is preferably pyrrolidinyl, piperidyl, lower alkyl-piperazinyl,morpholinyl or pyridyl.

If R₁ and R₂ together with the nitrogen atom to which they are attachedform a heterocyclic radical, the heterocyclic radical is as definedabove for a heterocyclic radical and represents preferably pyrrolidinyl,piperidyl, lower alkyl-piperazinyl, di-lower alkyl-piperazinyl ormorpholinyl.

An unsubstituted or substituted aromatic radical R₃ has up to 20 carbonatoms and is unsubstituted or substituted, for example in each caseunsubstituted or substituted phenyl. Preferably an unsubstitutedaromatic radical R₃ is phenyl. A substituted aromatic radical R₃ ispreferably phenyl substituted by one or more substituents selectedindependently of one another from the group consisting of unsubstitutedor substituted lower alkyl, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, N,N-di-lower alkanoylamino, hydroxy,lower alkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro, carboxy,lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthioand halogen. Most preferably a substituted aromatic radical R₃ is phenylsubstituted by one or more radicals selected independently of oneanother from the group consisting of lower alkyl, amino, hydroxy, loweralkoxy, halogen and benzyloxy.

Halogen is primarily fluoro, chloro, bromo or iodo, especially fluoro,chloro or bromo.

C₁-C₇-alkylene may be branched or unbranched and is in particularC₁-C₃-alkylene.

C₁-C₇-alkylene G is preferably C₁-C₃-alkylene, most preferably methylene(—CH₂—).

If G is not C₁-C₇-alkylene it preferably represents —C(═O)—.

C₁C₇-alkylene X is preferably C₁-C₃-alkylene, most preferably methylene(—CH₂—) or ethan-1,1-diyl (—CH(CH₃)—).

Q is preferably —NH—.

Z is preferably oxygen or sulfur, most preferably oxygen.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula I.

Special preference is given to a compound of formula I, wherein

-   R₁ and R₂ are each independently of the other hydrogen, lower alkyl,    hydroxy-lower alkyl, or a radical of the formula R₄—Y—(C═Z)— wherein    R₄ is di-lower alkylamino, pyrrolidinyl, piperidyl, lower    alkyl-piperazinyl, morpholinyl or pyridyl, Y is either not present    or lower alkyl and Z is oxygen, with the proviso that R₁ and R₂ are    not both hydrogen; or-   R₁ and R₂ together with the nitrogen atom to which they are attached    form a radical selected from the group consisting of pyrrolidinyl,    piperidyl, lower alkyl-piperazinyl, di-lower alkyl-piperazinyl and    morpholinyl;-   R₃ is phenyl, benzodioxolyl, pyridyl substituted by hydroxy or lower    alkoxy, or phenyl substituted by one or more radicals selected    independently of one another from the group consisting of lower    alkyl, hydroxy, lower alkoxy, halogen and benzyloxy;-   G is —CH₂—;-   Q is —NH—; and-   X is either not present, —CH₂— or —CH(CH₃)—, with the proviso that    substituted pyridyl R₃ is bonded via a ring carbon atom if X is not    present;-   or a salt thereof.

The compounds of formula I or salts thereof are prepared in accordancewith processes known per se (see also EP 682 027, WO 97/02266, WO97/27199 and WO 98/07726), though not previously described for themanufacture of the compounds of the formula I, especially whereby inorder to prepare a compound of formula I, wherein G is C₁-C₇-alkyleneand wherein R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, or a heterocyclicradical bonded via a ring carbon atom, with the proviso that R₁ and R₂are not both hydrogen, or wherein R₁ and R₂ together with the nitrogenatom to which they are attached form a heterocyclic radical, a compoundof the formula II

wherein Hal is halogen, G is C₁-C₇-alkylene and R₃, Q and X have themeanings as defined for a compound of formula I, is reacted with acompound of the formula III

wherein R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, or a heterocyclicradical bonded via a ring carbon atom, with the proviso that R₁ and R₂are not both hydrogen, or wherein R₁ and R₂ together with the nitrogenatom to which they are attached form a heterocyclic radical;whereby functional groups which are present in the starting compounds ofprocesses a) to d) and are not intended to take part in the reaction,are present in protected form if necessary, and protecting groups thatare present are cleaved, whereby the said starting compounds may alsoexist in the form of salts provided that a salt-forming group is presentand a reaction in salt form is possible;and, if so desired, a compound of formula I thus obtained is convertedinto another compound of formula I, a free compound of formula I isconverted into a salt, an obtained salt of a compound of formula I isconverted into the free compound or another salt, and/or a mixture ofisomeric compounds of formula I is separated into the individualisomers.

Description of the Process Variants

The reaction between a compound of formula II and a compound of formulaIII preferably takes place in a suitable inert solvent, especiallyN,N-dimethylformamide, in the presence of a base such as potassiumcarbonate, at temperatures from room temperature (RT) to 100° C.Alternatively, the reaction between a compound of formula II and acompound of formula III takes place in a suitable solvent, e.g. loweralcohols, such as ethanol, in the presence of for example a suitablecatalyst such as NaI, preferably at the reflux temperature of thesolvent employed. In a compound of formula II, Hal is preferably chloro.

Additional Process Steps

In the additional process steps, carried out as desired, functionalgroups of the starting compounds which should not take part in thereaction may be present in unprotected form or may be protected forexample by one or more protecting groups. The protecting groups are thenwholly or partly removed according to one of the known methods.

Protecting groups, and the manner in which they are introduced andremoved are described, for example, in “Protective Groups in OrganicChemistry”, Plenum Press, London, New York 1973, and in “Methoden derorganischen Chemie”, Houben-Weyl, 4th edition, Vol. 15/1,Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene,“Protective Groups in Organic Synthesis”, John Wiley & Sons, New York1981. A characteristic of protecting groups is that they can be removedreadily, i.e. without the occurrence of undesired secondary reactions,for example by solvolysis, reduction, photolysis or alternatively underphysiological conditions.

The end products of formula I may however also contain substituents thatcan also be used as protecting groups in starting materials for thepreparation of other end products of formula I. Thus, within the scopeof this text, only a readily removable group that is not a constituentof the particular desired end product of formula I is designated a“protecting group”, unless the context indicates otherwise.

General Process Conditions

All process steps described here can be carried out under known reactionconditions, preferably under those specifically mentioned, in theabsence of or usually in the presence of solvents or diluents,preferably those that are inert to the reagents used and able todissolve them, in the absence or presence of catalysts, condensingagents or neutralising agents, for example ion exchangers, typicallycation exchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to −60° C., at RT, at−20 to 40° C., at 0 to 100° C. or at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, if need be underpressure, and/or in an inert, for example an argon or nitrogen,atmosphere.

Starting Materials

The starting materials used in the above described processes a) to b)are known, capable of being prepared according to known processes (seealso EP 682 027, WO 97/02266, WO 97/27199 and WO 98/07726), orcommercially obtainable; in particular, they can be prepared usingprocesses as described in the Examples.

In the preparation of starting materials, existing functional groupswhich do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described above or in the Examples. Where the term startingmaterials is used hereinbefore and hereinafter, the salts thereof arealways included, insofar as reasonable and possible.

A compound of formula II can be prepared for example by reacting acompound of formula VII

wherein G is C₁-C₇-alkylene and R₃, Q and X have the meanings as definedfor a compound of formula I, with e.g. thionyl halogenide, preferablythionyl choride, in the presence or absence of pyridine, in an inertsolvent, for example toluene or in a 1:1 mixture of acetonitrile anddioxane, preferably at −10 to 0° C. or at RT.

A compound of formula VII can be prepared for example by reacting acompound of formula VIII

wherein R₅ is lower alkyl, especially methyl or ethyl, and R₃, Q and Xhave the meanings as defined for a compound of formula I, with lithiumaluminium hydride, in an inert solvent, especially ethers, e.g. cyclicethers such as tetrahydrofuran, preferably at the reflux temperature ofthe solvent employed. Alternatively, a compound of formula VII may beprepared by reacting a compound of formula VIII withdiisobutyl-aluminium hydride, in an inert solvent, for example intetrahydrofuran or in a 1:1 mixture of dichloromethane and dioxane,preferably at RT.

A compound of formula VIII wherein Q is —NH— can be prepared for exampleby reacting a compound of formula IX

wherein Hal is halogen, preferably chloro, and R₅ is as defined abovefor a compound of formula VIII, with a compound of the formula H₂N—X—R₃,wherein R₃ and X have the meanings as defined for a compound of formulaI, (i) in a suitable solvent such as alcohols, especially lower alcoholssuch as n-butanol, preferably at the boiling temperature of the solventemployed or (ii) under catalytic conditions.

A compound of formula VIII wherein Q is —O— can be prepared for exampleby reacting a compound of formula IX, which is preferably N-protected inthe pyrrolo-pyrimidine moiety, with a compound of the formula HO—X—R₃,wherein R₃ and X have the meanings as defined for a compound of formulaI, in a suitable inert solvent such as N,N-dimethylformamide and in thepresence of a base such as potassium carbonate, at elevatedtemperatures, preferably at around 100° C.

Alternatively, the carboxylic acid ester of a compound of formula IX mayfirst be reduced to the corresponding alcohol, e.g. under conditionsdescribed above for the preparation of a compound of formula VII, andthen either be reacted with a compound of the formula H₂N—X—R₃, e.g.under conditions described above for the preparation of a compound offormula VIII wherein Q is —NH—, or be reacted with a compound of theformula HO—X—R₃, e.g. under conditions described above for thepreparation of a compound of formula VIII wherein Q is —O—.

A compound of formula I, or a pharmaceutically acceptable salt thereof,can be used in pharmaceutical compositions known as such. Compositionsfor enteral administration, such as nasal, buccal, rectal or,especially, oral administration, and for parenteral administration, suchas intravenous, intramuscular or subcutaneous administration, towarm-blooded animals, especially humans, are especially preferred. Thecompositions contain the active ingredient alone or, preferably,together with a pharmaceutically acceptable carrier. The dosage of theactive ingredient depends upon the disease to be treated and upon thespecies, its age, weight, and individual condition, the individualpharmacokinetic data, and the mode of administration. The pharmaceuticalcompositions comprise from approximately 1% to approximately 95% activeingredient, single-dose administration forms comprising in the preferredembodiment from approximately 20% to approximately 90% active ingredientand forms that are not of single-dose type comprising in the preferredembodiment from approximately 5% to approximately 20% active ingredient.Unit dose forms are, for example, coated and uncoated tablets, ampoules,vials, suppositories or capsules. Examples are capsules containing fromabout 0.05 g to about 1.0 g of active substance.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional mixing,granulating, coating, dissolving or lyophilising processes.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference.

In one preferred embodiment of the invention, the solid tumor disease tobe treated is renal cell cancer. In another preferred embodiment of theinvention, the solid tumor disease to be treated is NSCLC. In a furtherpreferred embodiment of the invention, the solid tumor disease to betreated is selected from skin squamous cell carcinoma and head and necksquamous cell carcinoma. In another preferred embodiment of theinvention, the solid tumor disease is anorectal cancer, especiallyanorectal adenocarcinoma and squamous cell carcinoma of the anal canaland margin and metastasis thereof.

In one embodiment the present invention relates to a treatment regimenwhereby the 7H-pyrrolo[2,3-d]pyrimidine derivative is administered tothe human subject less frequently than on a daily basis. In particular,the present invention relates to a treatment regimen whereby over atleast a three week period, the 7H-pyrrolo[2,3-d]pyrimidine derivative isadministered on only about 40% to about 71% of the days. In suchembodiment, specifically, the present invention relates to a method oftreating a human subject with a 7H-pyrrolo[2,3-d]pyrimidine derivative,which comprises administering such pyrimidine derivative to the humansubject from three to five times in each seven day period for a periodof three weeks or longer, more specifically, three or four times a weekon alternate days for a period of three weeks or longer. In a specificembodiment, the 7H-pyrrolo[2,3-d]pyrimidine derivative is administeredthree times each week on alternate days, for example, on Monday,Wednesday and Friday of each week, for at least three weeks. Thus, the7H-pyrrolo[2,3-d]pyrimidine derivative is administered every other dayuntil three doses are given and the next dose is administered at thebeginning of the following week. Preferably, such dosage regimen iscarried out through at least four or more weeks, for example 4, 5, 6, 7or 8 weeks. Alternatively, the 7H-pyrrolo[2,3-d]pyrimidine derivative isadministered daily for a period of one to three weeks, e.g. two weeks,followed by a period of one to three weeks, e.g. two weeks withoutadministering the compound to the patient.

Thus, the present invention relates especially to a method of treating asolid tumor disease as defined herein, which comprises administering apharmaceutically effective amount of(R)-6-(4-hydroxy-phenyl)-4-[(1-phenyl-ethyl)-amino]-7H-pyrrolo[2,3-d]pyrimidine,or a salt thereof, to a human subject, preferably three or four times aweek on alternate days, more preferably three times a week on alternatedays, for a period of three weeks or longer.

The inventive dosage regimen applies to the use of7H-pyrrolo[2,3-d]pyrimidine derivative, for example, PKI166, alone, oras part of a combination treatment therapy wherein it is co-administeredwith one or more additional pharmaceutical products useful for treatingtumors, especially cancerous tumors. For purposes of this applicationco-administered means that the patient is treated with both drugsaccording to the proper schedule for each, but not necessarily that bothdrugs are administered together at the same time. Thus, the7H-pyrrolo[2,3-d]pyrimidine derivative, may be administered alone or incombination with other anticancer agents, e.g. in accordance with thepresent inventive dosage regimen.

The 7H-pyrrolo[2,3-d]pyrimidine derivative is advantageouslyadministered to the human subject at a pharmaceutically effective dosagein the range of from about 50 mg to about 2000 mg on days when the7H-pyrrolo[2,3-d]pyrimidine derivative is administered. When PKI166 isemployed, the preferred effective dose is in the range from about 50 mgto about 2000 mg, for example, about 450 mg to about 1500 mg doses orabout 500 mg to about 1200 mg doses.

The 7H-pyrrolo[2,3-d]pyrimidine derivative is administered to thesubject by methods known in the art for administering pharmaceuticalproducts, for example, orally, rectally or parenterally, preferablyorally as a tablet or capsule formulation. Especially, the7H-pyrrolo[2,3-d]pyrimidine derivative can be administered as describedin WO 97/02266.

The effect of a 7H-pyrrolo[2,3-d]pyrimidine derivative against the tumortypes mentioned herein can be demonstrated, e.g., in suitable tumormodels utilising cells lines, e.g. models utilising the cell linesNCI-H529 SCC (lung) or orthotopic 253J B-V (bladder).

The following Examples illustrate the invention described above; theyare not, however, intended to limit the scope of the invention in anyway. The beneficial effects of the 7H-pyrrolo[2,3-d]pyrimidinederivatives can also be determined by other test models known as such tothe person skilled in the pertinent art.

EXAMPLES Example 1{6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine

A mixture of 10.8 g (30 mmol)[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-aminein 450 ml DMF is treated with 6.8 ml (63 mmol) N-methyl-piperazine and20.7 g (150 mmol) anhydrous potassium carbonate and the mixture heatedto 65° C. for 1 hour. The reaction mixture is cooled and the inorganicsalts removed by filtration (Hyflo Super Cel®; Fluka, Buchs,Switzerland). The DMF is evaporated under reduced pressure and theresidue purified through flash chromatography using firstdichloro-methane/ethanol 9:1 and then dichloromethane/ethanol 9:1 plus1% conc. ammonia. Crystallization of the pure fractions from THF (20 ml)and hexanes (80 ml) gives the title compound; m.p. 248-250° C.; MS-ES⁺:(M+H)⁺=427.

Step 1.1:4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester

1.8 g (6 mmol) 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acidethyl ester (WO 97/02266) are suspended in 40 ml n-butanol and treatedwith 1.5 ml (12 mmol) (R)-phenethylamine. The mixture is heated to 145°C. under stirring. After 3 h a clear brown solution is obtained which istreated with a second portion of (R)-phenethylamine (0.75 ml, 6 mmol).After stirring for additional 2 h the reaction mixture is cooled in anice bath and the title compound filtered and washed with cold n-butanoland ether; m.p. 288-290° C.

Step 1.2:{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol

570 mg (15 mmol) lithium aluminum hydride are suspended in 150 ml dryTHF at RT. 1.23 g (3-mmol)4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoicacid ethyl ester are added and the mixture heated to reflux for 1 h. Themixture is cooled in an ice bath and treated sequentially with water(0.57 ml), 15% sodium hydroxide solution (0.57 ml) and water (1.71 ml).The solid aluminum complex is removed by filtration (Hyflo Super Cel®;Fluka, Buchs, Switzerland), the filtrate dried over sodium sulfateevaporated. The residue is suspended in water, filtered and dried togive the title compound; m.p. >300° C.; R_(f) (dichloromethane/ethanol9:1 plus 1% conc. ammonia)=0.43.

Step 1.3:[6-(4-Chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine

A solution of thionyl chloride (25.7 ml, 0.328 mol) in 180 ml of tolueneis cooled to −10° C. Solid{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol(11.3 g, 0.0328 mol) is added in 8 portions over a range of 1 h. Thetemperature is then increased slowly to 0° C. and the mixture stirredfor 2 h. The cold reaction mixture is filtered and the solid washed withtoluene and ether. The crude product is suspended in water and treatedwith saturated sodium bicarbonate solution until the mixture turnsbasic. The mixture is stirred well for about 10 min and filtered. Thesolid is thoroughly washed with water and dried under reduced pressureto give the title compound; m.p. >320° C.; R_(f)(dichloromethane/ethanol 9:1)=0.46.

Examples 2-10

The following Examples are synthesized from[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amineusing an analogous procedure described in Example 1: Exam- m.p. ple Name[° C. ] 2 [6-(4-Diethylaminomethyl-phenyl)-7H-pyrrolo[2,3- 246-248d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine 3{6-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-7H- 245-247pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)- amine 4((R)-1-Phenyl-ethyl)-[6-(4-pyrrolidin-1-ylmethyl- 254-256phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 5[6-(4-Dimethylaminomethyl-phenyl)-7H- 241-243pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)- amine 6((R)-1-Phenyl-ethyl)-[6-(4-piperidin-1-ylmethyl- 246-248phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine 7[6-(4-Morpholin-4-ylmethyl-phenyl)-7H- 263-265pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)- amine 8{6-[4-(3,5-Dimethyl-piperazin-1-ylmethyl)-phenyl]- 208-2107H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phenyl- ethyl)-amine 9(6-{4-[(2-Morpholin-4-yl-ethylamino)-methyl]- 222-224phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-((R)-1- phenyl-ethyl)-amine 10((R)-1-Phenyl-ethyl)-(6-{4-[(tetrahydro-pyran-4- 253-255ylamino)-methyl]-phenyl}-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amine

Example 11

A human patient suffering from renal cell cancer is treated for a periodof 16 weeks in 4 cycles consisting of administration of 600 mg of PKI166daily for two weeks followed by 2 weeks without administering the drug.During such 16 weeks a stable disease is observed.

Example 12

A human patient suffering from renal cell cancer is treated for a periodof 16 weeks with 400 mg of PKI166 on Monday, Wednesday and Friday ofeach week. During such 16 weeks a stable disease is observed.

Example 13

A human patient suffering from NSCLC is treated for a period of 8 weekswith 450 mg/day of PKI166 except on day 2, 16 and 30 on which days nodrug is applied. After such treatment a partial response is observed.

1-14. (canceled) 15: The use of a 7H-pyrrolo[2,3-d]pyrimidine derivativeof the following formula (I′)

wherein q is 0 or 1; n is from 1-3 when q is 0, or n is from 0-3 when qis 1; R is halogen, lower alkyl, hydroxy, lower alkanoyloxy, lowerafkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, cyano, amino, loweralkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortri-fluoromethyl, it being possible when several radicals R are presentin the molecule for those radicals to be identical or different; a) R₁and R₂ are each independently of the other α) phenyl substituted bycarbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, loweralkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, loweralkylamino, N,N-di-lower alkylamino, hydroxy, lower alkanoyloxy,carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl,N,N-di-lower alkyl-carbamoyl, cyano or by nitro; β) hydrogen with theproviso that R₁ and R₂ are not hydrogen simultaneously; γ) unsubstitutedor halo- or lower alkyl-substituted pyridyl; δ)N-benzyl-pyridinium-2-yl, naphthyl, cyano, carboxy, loweralkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, N-benzyl-carbamoyl, formyl, lower alkanoyl, loweralkenyl, lower alkenyloxy; or ε) lower alkyl substituted by εα) halogen,amino, lower alkylamino, piperazino, di-lower alkylamino, εβ)phenylamino that is unsubstituted or substituted in the phenyl moiety byhalogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy,lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-loweralkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino,N,N-di-lower alkylamino or by trifluoromethyl, εγ) hydroxy, loweralkoxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, mercapto or εδ) by aradical of the formula R₃—S(O)m-, wherein R₃ is lower alkyl and m is 0,1 or 2; or b) when q is 0, one of the radicals R₁ and R₂ isunsubstituted lower alkyl or unsubstituted phenyl and the other of theradicals R₁ and R₂ has one of the meanings given above in paragraph a)with the exception of hydrogen; or c) when q is 0 and R is carboxy,carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl orlower alkanoyl-amino, R₁ and R₂ together are C₄-C₁₀-1,4-alkadienylenesubstituted by amino, lower alkanoylamino, lower alkylamino,N,N-di-lower alkylamino, nitro, halogen, hydroxy, lower alkanoyloxy,carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl,N,N-di-lower alkyl-carbamoyl or by cyano, or are aza-1,4-alkadienylenehaving up to 9 carbon atoms; or d) when q is 1, R₁ and R₂ are eachindependently of the other unsubstituted lower alkyl or unsubstitutedphenyl or have one of the meanings given above in paragraph a), and R₆is hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N-loweralkyl-carbamoyl or N,N-di-lower alkyl-carbamoyl, with the exception ofthe compound of formula (I), wherein n is 0, q is 1, R₁ and R₆ are eachhydrogen and R₂ is methyl, the compound of formula (I′), wherein n is 2,q is 1, R₁ and R₆ are each hydrogen, R₂ is methyl and R is 3,4-methoxyand the compounds of formula (I′), wherein n is 1, q is 0, R₁ is3-pyridyl, 4-cyanophenyl or 4-hydroxyphenyl, R₂ is hydrogen and R isfluoro, and wherein the prefix “lower” denotes a radical having up toand including a maximum of 7 carbon atoms; or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for thetreatment of renal carcinoma. 16: The use according to claim 15, whereinthe 7H-pyrrolo[2,3-d]pyrimidine derivative of formula (I′) is(R)-6-(4-hydroxy-phenyl)-4-[(1-phenyl-ethyl)-amino]-7H-pyrrolo[2,3-d]pyrimidine.17: A method for the treatment of patient suffering from renal carcinomacomprising administering a pharmaceutically effective amount of a7H-pyrrolo[2,3-d]pyrimidine derivative of formula (I′) according toclaim 15, or a pharmaceutically acceptable salt thereof, to the patient.18: The method of claim 17, wherein the pharmaceutically effective doseis in the range from about 50 mg to about 2000 mg. 19: A method ofinhibiting metastatic growth in a patient with a renal carcinoma whichcomprises administering a pharmaceutically effective amount of a7H-pyrrolo[2,3-d]pyrimidine derivative of formula (I′) according toclaim 15, or a pharmaceutically acceptable salt thereof, to the patient.20: Use of a 7H-pyrrolo[2,3-d]pyrimidine derivative of formula (I)

wherein R₁ and R₂ are each independently of the other hydrogen,unsubstituted or substituted alkyl or cycloalkyl, a heterocyclic radicalbonded via a ring carbon atom, or a radicat of the formula R₄—Y—(C═Z)—,wherein R₄ is unsubstituted, mono- or disubstituted amino or aheterocyclic radical, Y is either not present or lower alkyl and Z isoxygen, sulfur or imino, with the proviso that R₁ and R₂ are not bothhydrogen; or R₁ and R₂, together with the nitrogen atom to which theyare attached, form a heterocyclic radical; R₃ is a heterocyclic radicalor an unsubstituted or substituted aromatic radical; G isC₁-C₇-alkylene, —C(═O)—, or C₁-C₆-alkylene-C(═O)—, wherein the carbonylgroup is attached to the NR₁R₂ moiety; Q is —NH— or —O—, with theproviso that Q is —O— if G is —C(═O)— or C₁-C₆-alkylene-C(═O)—; and X iseither not present or C₁-C₇-alkylene, with the proviso that aheterocyclic radical R₃ is bonded via a ring carbon atom if X is notpresent; or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of carcinoma of thebladder, renal carcinoma, squamous cell carcinoma of the skin, tumors ofthe gastrointestinal tract, mesothelioma, esophageal tumors, stomachcancer, small-bowel tumors and large-bowel tumors such as polyps of thecolon and rectum and anorectal cancer. 21: A method for the treatment ofpatients suffering from a solid tumor disease selected from carcinoma ofthe bladder, renal carcinoma, squamous cell carcinoma of the skin,tumors of the gastrointestinal tract, mesothelioma, esophageal tumors,stomach cancer, small-bowel tumors and large-bowel tumors, such aspolyps of the colon and rectum and anorectal cancer, comprisingadministering to the patient a pharmaceutically effective amount of a7H-pyrrolo[2,3-d]pyrimidine derivative of formula (I) according to claim20 or a pharmaceutically acceptable salt of said compound. 22: Themethod of claim 21, wherein the pharmaceutically effective dose is inthe range from about 50 mg to about 2000 mg. 23: A method of inhibitingmetastatic growth in a patient with a solid tumor disease selected fromcarcinoma of the bladder, renal carcinoma, squamous cell carcinoma ofthe skin, tumors of the gastrointestinal tract, mesothelioma, esophagealtumors, stomach cancer, small-bowel tumors and large-bowel tumors, suchas polyps of the colon and rectum and anorectal cancer which comprisesadministering to the patient a pharmaceutically effective amount of a7H-pyrrolo[2,3-d]pyrimidine derivative of formula (I) according to claim20 or a salt of the said compounds, for the treatment of carcinoma ofthe bladder, renal carcinoma, squamous cell carcinoma of the skin,tumors of the gastrointestinal tract, mesothelioma, esophageal tumors,stomach cancer, small-bowel tumors and large-bowel tumors, such aspolyps of the colon and rectum and anorectal cancer.